Throughout this application the following standard abbreviations are used to refer to amino acids:
______________________________________ Alanine Ala A Glutamate Glu E Glutamine Gln Q Aspartate Asp D Asparagine Asn N Leucine Leu L Glycine Gly G Lysine Lys K Serine Ser S Valine Val V Arginine Arg R Threonine Thr T Proline Pro P Isoleucine Ile I Methionine Met M Phenylalanine Phe F Tyrosine Tyr Y Cysteine Cys C Tryptophan Trp W Histidine His H Ornithine Orn ______________________________________
Gene transfer technology has become a field of considerable interest. Introduction of an exogeneous gene into a cell (i.e. transfection) bears many important scientific and medical applications, going from gene regulation and the production of recombinant proteins to gene therapy.
Viruses have evolved to bypass the different cellular barriers to gene transfer and have indeed become vectors of choice for transfection. Many viruses, including retrovirus, adenovirus or herpes virus, are now engineered to carry therapeutic genes and used in human clinical trials for gene therapy. However, there remains a risk of infectious and immunologic reaction and the large scale production of viruses is difficult and time consuming.
For these various reasons non viral systems have been developed to carry DNA into cells, e.g., the transfection technique based on a cationic lipid, the dioleoyloxypropyl trimethylammonium (Felgner et al., Proc. Natl., Acad. Sci. U.S.A., 84, 7413-7417, 1987) commercialized as Lipofectin.TM.. Since the discovery of this transfection technique, many more cationic lipids have been synthesized and some are commercially available as transfecting reagent for laboratory use: DOGS (Transfectam.TM.), DOSPA (Lipofectamine.TM.), DOTAP (DOTAP.TM.).
Nevertheless, despite important progress in the formulation of non-viral gene delivery systems, there remains a need for more efficient techniques, since the transfection efficiency of synthetic systems is usually below that of viral vectors. Furthermore, many problems still arise in vivo, and the poor stability of the non-viral systems in biological fluids does not allow high and reproducible levels of transfection in vivo.
Cell-lytic antibacterial peptides that act by perturbing the barrier function of membranes are reviewed in Saberwal, et al., Biochim. Biophys. Acta. (1994) 1197:109-131. Certain fatty acid-bearing basic peptides having antibacterial activity are disclosed in Vogler, et al., Helv. Chim. Acta (1964) 47:526-543. Poly(lysine-serine) random polymers for use as carriers to transport oligonucleotides into a cell is disclosed in European Patent Publication No. EP 0 727 223.